The actions of caloric restriction (CR) on lifespan are long-known and well-described. Many mechanisms for this relationship have been postulated and studied, however none has emerged as a sole explanation for CR's actions. Characteristics that transcend multiple models of CR actions may or may not be related to a single origin. The purpose of this dissertation was to describe the actions of ghrelin, a protein hormone known to have similar effects as the actions of CR and its levels to be changed during CR, in multiple mouse and human CR-like studies. Mouse models of varying severities of traditional CR, CR mimetics, or potential CR mechanisms provided systems for ghrelin-CR evaluation in the first two studies of this dissertation. In the third study, polymorphic variation in the promoter region of the ghrelin receptor gene and protein levels of ghrelin and other metabolic peptides were evaluated in a human CR condition: Roux-en-Y gastric bypass surgery. Ghrelin was demonstrated to have nuanced effects in models or mimetics of CR. Ghrelin did not increase consistently with increasing levels of CR or generally in CR mimetics. Ghrelin did show differential effects between sexes in mice and secondly, polymorphisms in the promoter region of its receptor gene were associated with different weight loss trajectories one year post-surgery in gastric bypass patients. Therefore, there may be some role for ghrelin or the ghrelin signaling pathway during CR models, and particularly describing how genetic changes affect clinical outcomes in the obese surgical population warrants further attention.